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Effect of the cross-talk between autophagy and endoplasmic reticulum stress on Mn-induced alpha-synuclein

Chang Liu¹, Dong-Ying Yan¹, Xuan Tan¹

¹Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, People's Republic of China.

Environmental Toxicology

|December 2, 2017

Abstract:

Overexposure to manganese (Mn) has been known to induce alpha-synuclein (α-Syn) oligomerization, which is degraded mainly depending on endoplasmic reticulum stress (ER stress) and autophagy pathways. However, little data reported the cross-talk between ER stress and autophagy on Mn-induced α-Syn oligomerization. To explore the relationship between ER stress and autophagy, we used 4-phenylbutyric acid (4-PBA, the ER stress inhibitor), rapamycin (Rap, autophagy activator) and 3-methyladenine (3-MA, autophagy inhibitor) in mice model of manganism. After 4 weeks of treatment with Mn, both ER stress and autophagy were activated. Exposed to Mn also resulted in α-Syn oligomerization and neuronal cell damage in the brain tissue of mice, which could be relieved by 4-PBA pretreatment. Moreover, when the ER stress was inhibited, the activation of autophagy was also inhibited. Rap pretreatment significantly activated autophagy and decreased α-Syn oligomers. However, 3-MA pretreatment inhibited autophagy resulting in increase of α-Syn oligomers, and compensatorily activated PERK signaling pathway. Our results also demonstrated that the inhibition of autophagy by 3-MA aggravated neuronal cell damage. The findings clearly demonstrated that the cross-talking between autophagy and ER stress might play an important role in the α-Syn oligomerization and neurotoxicity by Mn.

Insights

Manganese (Mn) exposure triggers alpha-synuclein (α-Syn) buildup and neurotoxicity. This study reveals that endoplasmic reticulum (ER) stress and autophagy pathways are interconnected, influencing Mn-induced α-Syn oligomerization.

Area of Science:

Neuroscience
Toxicology
Cell Biology

Background:

Manganese (Mn) overexposure is linked to alpha-synuclein (α-Syn) oligomerization.
Endoplasmic reticulum (ER) stress and autophagy are key degradation pathways for α-Syn.
The interplay between ER stress and autophagy in Mn-induced neurotoxicity is not well understood.

Purpose of the Study:

To investigate the relationship between ER stress and autophagy in the context of Mn-induced α-Syn oligomerization.
To explore the therapeutic potential of modulating ER stress and autophagy pathways.

Main Methods:

Utilized a mouse model of manganism treated with Mn.
Administered ER stress inhibitor (4-phenylbutyric acid, 4-PBA), autophagy activator (rapamycin, Rap), and autophagy inhibitor (3-methyladenine, 3-MA).
Assessed α-Syn oligomerization, ER stress markers, autophagy activation, and neuronal cell damage.

Main Results:

Mn exposure activated both ER stress and autophagy, leading to α-Syn oligomerization and neuronal damage.
Inhibiting ER stress with 4-PBA reduced α-Syn oligomers and neuronal damage, and also suppressed autophagy.
Activating autophagy with Rap decreased α-Syn oligomers, while inhibiting autophagy with 3-MA increased α-Syn oligomers and aggravated neuronal damage, with compensatory PERK pathway activation.

Conclusions:

Cross-talk between ER stress and autophagy plays a significant role in Mn-induced α-Syn oligomerization.
Modulating ER stress and autophagy pathways holds potential for mitigating Mn neurotoxicity.
Understanding this interplay is crucial for developing therapeutic strategies against manganese-related neurodegenerative disorders.

Read full analysis

Keywords:

alpha-synuclein oligomerization autophagy endoplasmic reticulum stress manganese

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